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Studies on using mucinous glycoprotein promising for cartilage treatments
Our Chief Medical Editor, Douglas W. Jackson, MD, poses 4 Questions to Carl R. Flannery, PhD, about the use of lubricin for cartilage degeneration.
The superficial layers of articular cartilage are often where the early signs of degenerative changes occur. As clinicians, we will be hearing more about an important mucinous glycoprotein (lubricin) that has protective characteristics on these superficial layers.
I have asked a recognized expert, Carl R. Flannery, PhD, to share his insight into what lubricin actually is and what are some areas it may see clinical application.
Douglas W. Jackson, MD
Chief Medical Editor
Douglas W. Jackson, MD: What is lubricin and how is it connected to joint function?
Carl R. Flannery, PhD: Lubricin is a secreted, mucinous glycoprotein, originally identified in synovial fluid. Some of its principal functions, such as boundary lubrication and tissue protection, are directly related to its ability to absorb to and coat cartilage surfaces. The protein backbone and attached sugar chains of lubricin resemble polymer “brushes” which help reduce cartilage friction and wear. Lubricin also appears to interact with hyaluronan, thereby contributing to the mechanical properties of synovial fluid.
Jackson: Why are there other names for this macromolecule (ie, SZP and PRG4) and which is the preferred usage?
Flannery: The name lubricin was first introduced over a quarter-century ago to describe a lubricating glycoprotein prepared from synovial fluid. Its molecular identity, however, was determined only relatively recently. In 1999, the sequence of a cartilage “superficial zone protein” (SZP) was reported, which was found to be homologous to a protein that is mutated in patients with the rare heritable disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP). Concurrently, it was determined that the amino acid sequence of lubricin purified from synovial fluid matched that of SZP/CACP protein, indicating that these molecules, discovered independently, are products of the same gene. This gene was assigned the name “Proteoglycan 4” (PRG4). The term “lubricin” acknowledges a compelling legacy and is commonly used.
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Jackson: How does lubricin interact with other macromolecules in the joint, such as hyaluronan (HA)?
Flannery: Interactions involving the carboxy-terminal domain of lubricin seem to be important for binding to cartilage surfaces. Lubricin monomers may also self-assemble via amino-terminal domain interactions, and such multimerization is likely to be important in providing molecular organization for function. In synovial fluid, lubricin has been shown to contribute to the structuring of HA polymers. Details of how such lubricin-HA interactions may occur remain to be fully investigated.
Jackson: How close are we to a clinical use for lubricin in our patients with degenerative articular cartilage changes?
Flannery: Early proof-of-concept studies, demonstrating binding and lubrication of cartilage by purified lubricin (including recombinant lubricin generated at Wyeth), are encouraging. In preclinical studies, we have also observed that intraarticular supplementation with a recombinant lubricin injectable is efficacious in preventing the progression of surgically-induced osteoarthritis. These findings provide further support for the concept of developing lubricin as a biotherapeutic to treat degenerative joint disease.
For more information:
- Carl R. Flannery, PhD, can be reached at Wyeth Research, 200 Cambridge-Park Drive, Cambridge, MA 02140; 617-665-5341; e-mail: cflannery@wyeth.com. He is an employee of Wyeth.